title: Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal.
abstract: Many forms of apoptosis, including that caused by the death receptor CD95/Fas/APO-1, depend on the activation of caspases, which are proteases that cleave specific intracellular proteins to cause orderly cellular disintegration. The requirements for activating these crucial enzymatic mediators of death are not well understood. Using molecular chimeras with either CD8 or Tac, we find that oligomerization at the cell membrane powerfully induces caspase-8 autoactivation and apoptosis. Death induction was abrogated by the z-VAD-fmk, z-IETD-fmk, or p35 enzyme inhibitors or by a mutation in the active site cysteine but was surprisingly unaffected by death inhibitor Bcl-2. Amino acid substitutions that prevent the proteolytic separation of the caspase from its membrane-associated domain completely blocked apoptosis. Thus, oligomerization at the membrane is sufficient for caspase-8 autoactivation, but apoptosis could involve a death signal conveyed by the proteolytic release of the enzyme into the cytoplasm.
authors.affiliation: Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1892, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Martin
authors.forename: R M
authors.initials: RM
authors.lastname: Siegel
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.forename: M J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D017209:Apoptosis; D001704:Biopolymers; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D006868:Hydrolysis; D015398:Signal Transduction
chemical_list: D001704:Biopolymers; D015853:Cysteine Proteinase Inhibitors; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases